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Genomic instability and accumulation of mutations is one of the features of cancer. In order to preserve genome integrity, cells require several evolutionary conserved processes, such as the DNA damage response and cell cycle checkpoints.¹ In fact, the DNA damage response has been proposed to constitute an earlier barrier to tumorigenesis.^2,3 However, the mechanism(s) by which cells maintain genome integrity, in particular a diploid complement, remain poorly understood.

In a previous issue of Cell Cycle, Bunz and colleagues set out to investigate the role of Chk1 in the preservation of stable ploidy.⁴ Using isogenic colorectal cancer cell lines that differ in p53 status, the authors generated cell lines hemizygous for CHK1 (homozygous CHK1-null cells are not viable) and show that CHK1 haploinsufficiency in a p53-deficient background leads to the appearance of a tetraploid subpopulation.⁴ Interestingly, CHK1 haploinsufficiency led to tetraploidization via mitotic bypass and subsequent whole-genome endoreduplication.⁴

Chk1 is a Ser/Thr kinase essential for cell viability, possibly through its role in monitoring the proper execution of DNA replication and mitosis.⁵ However, the role of Chk1 in these processes is still unclear. Hints of its role have emerged in experiments following exogenous DNA damage stimuli. Under these conditions, the upstream kinase ATR rapidly activates Chk1, which, in turn, will phosphorylate numerous downstream substrates promoting the coordination of DNA repair with cell cycle progression.^5,6

In unperturbed cells, Chk1 can also be found associated with chromatin and phosphorylates Thr11 in histone H3, leading to its acetylation at Lys9, a mark of transcriptionally active regions.⁷ Upon DNA damage, Chk1 disengages from chromatin with two main consequences: a decrease of histone H3 phosphorylation, leading to repression of transcription of key cell cycle regulators,⁷ and an increase of inhibitory phosphorylations of CDC25, a positive regulator of cell cycle progression.⁸ This one-two punch highlights the central role of Chk1 in regulating cell cycle progression.

Three main mechanisms have been proposed to explain tetraploidization in cancer: cell fusion, defects in mitosis and endoreduplication.⁹ Endoreduplication has been attributed to persistent ATM/ATR-mediated DNA damage signaling resulting from telomere dysfunction, DNA repair defects or oncogene overexpression.⁹ Bunz and colleagues now propose a distinct mechanism to achieve tetraploidization: high frequency of mitotic bypass due to decreased CHK1 gene dosage in p53-deficient cells. The authors demonstrate that this phenotype is ATR-independent and likely not due to DNA damage-induced effects. In fact, endogenous DNA damage levels, as judged by 53BP1 and phospho-H2AX nuclear foci formation, were similar in CHK1^+/− and parental cells, showing that decreased levels of Chk1 by itself do not lead to a substantial increase in DNA damage.⁴

So, what mediates mitotic bypass caused by CHK1 haploinsufficiency? Because Cdk1 (also known as cdc2) has been shown to control entry to mitosis, the authors hypothesized that normal levels of Chk1 might be required for full activation of Cdk1. Indeed, in p53-deficient CHK1^+/− cells, Cdk1 activity was diminished when compared with parental p53-deficient CHK^+/+ cells. Moreover, stable overexpression of Cdk1 in a p53-deficient CHK1^+/− background suppressed the formation of tetraploid cells. Whether the observed effect of CHK1 haploinsufficiency on Cdk1 activity is direct or not awaits further investigation.

In summary, the study by Bunz and colleagues shows that CHK1 haploinsufficiency may play an important role in tumorigenesis by promoting genetic instability in cells that are p53-deficient. This work opens up a new front in the study of mechanisms of mitotic bypass and highlights the power of genetic analysis using somatic knockout approaches. The Bunz laboratory has made seminal contributions to the development of these methods and is particularly well positioned to make further inroads into these difficult-to-tackle problems.

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